O1‐06–04: Methylthioninium chloride (MTC) acts as a Tau aggregation inhibitor (TAI) in a cellular model and reverses Tau pathology in transgenic mouse models of Alzheimer's disease

内嗅皮质 海马体 转基因小鼠 下托 化学 皮质(解剖学) 神经科学 老年斑 扁桃形结构 脾后皮质 病理 阿尔茨海默病 分子生物学 细胞生物学 生物 转基因 生物化学 医学 齿状回 疾病 基因
作者
Charles R. Harrington,Janet E. Rickard,David A. Horsley,Kathleen A. Harrington,Kathleen P. Hindley,Gernot Riedel,Franz Theuring,Kwang Meng Seng,Claude M. Wischik
出处
期刊:Alzheimers & Dementia [Wiley]
卷期号:4 (4S_Part_4) 被引量:21
标识
DOI:10.1016/j.jalz.2008.05.259
摘要

MTC not only blocks the formation of Tau oligomers and their conversion to Paired Helical Filaments (PHFs), but can also dissolve Tau aggregates into the truncated repeat domain monomers that comprise the PHF core. Importantly, it does not affect normal Tau-Tubulin interaction which also occurs through the repeat domain. We have examined whether MTC can affect pathological processing of Tau in cellular and animal models. An inducible model of Tau aggregation in cell culture and two distinct transgenic mouse lines were generated. In one mouse, a repeat domain Tau fragment was directed to the endoplasmic reticulum to seed an artificial nucleation event. In a second line, mice expressed mutant Tau. The brains were examined, following 2–3 weeks treatment with oral MTC, for Tau pathology using mAb 7/51. The pathological processing of Tau in the human brain has been reproduced in a cell model in vitro. MTC inhibits this process with an EC50 of 0.59 μM, a value substantially less than that required to inhibit Tau-Tau binding in vitro. MTC also dissolves PHFs isolated from the brain with an EC50 of 0.13 μM. Postmortem examination of brain tissue from mice expressing truncated Tau showed significant reduction in counts of Tau-positive neurons in hippocampus and entorhinal cortex, regions believed to be important in spatial learning tasks. Regions with abundant pathology in mice expressing mutant tau include visual cortex, hippocampus, entorhinal cortex and subiculum, whereas less abundant pathology in “low count regions” was observed in amygdala, auditory cortex and retrosplenial cortex. Histopathological analysis showed that MTC (2 or 5 mg/kg/day) given intravenously for 17 days reduced pathology in both models. In the mutant Tau mice, the lower dose produced reduction in the low count regions, whereas those areas having greater pathology required a higher dose (5 mg/kg/day). MTC serves as a Tau Aggregation Inhibitor in vivo both in a cellular assay, suitable for screening further TAIs, and in two distinct transgenic mouse models. In the mice, brief treatment with MTC produced a reversal of Tau pathology, the extent of which depended upon the amount of pathology in the brain.
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